1. Field of the Invention
This invention relates generally to drug delivery systems and methods, and more particularly to tissue penetrating drug delivery compositions.
2. Description of the Prior Art
Traditional systems for the delivery of drugs and other agents into the body each pose particular problems to the proper administration of the drug or agent. Oral administration subjects the drug or agent to the acidic environment of the stomach, where the drug or agent sometimes is chemically degraded. Enzymes in the gastrointestinal tract, surrounding tissue, or in the liver can destroy much of the drug before it enters the systemic circulation. Some drugs, although able to withstand the destructive environment of the gastrointestinal tract, are nonetheless poorly absorbed through the gastrointestinal tract. High doses of a drug must often be utilized when given orally in order to achieve a desired local concentration.
Hypodermic injection and intraveneous infusion can cause infection and bruising. Controlled release of the drug over a period of time is generally not possible with this form of administration.
Rectal administration is usually accomplished through solid or semi-solid suppositories. These suppositories dispose the drug or agent in a base composition which melts gradually at body temperatures to release the drug or agent. The base composition, however, must usually be kept at low temperatures before use to preserve a fixed shape for proper insertion into the body. The base composition, when melted in the body, can form a film on the surrounding membrane of the body to suppress the desired absorption of the drug or agent into the body. The suppository is discomforting to patients, is difficult to insert, and sometimes is excreted in the original state so that little or none of the drug or agent will be absorbed by the body.
It is known that some of the problems associated with traditional forms of drug administration can be avoided by the use of administration systems and compositions which aim to pass the drug through the skin or other tissue of the body by intercellular and intracellular diffusion. It is known that diffusion is an effective method of application of drugs and agents to the skin for the treatment of a number of dermal conditions. These conditions include pruritus, acne, herpes simplex, psoriasis, and skin cancer. Transdermal diffusion is also useful for the application of cosmetics and sunblocking agents to insure their retention in the skin. It is further well-known that a number of drugs and agents can be administered through the skin or other body tissues for systemic circulation.
Drug application by tissue penetration is particularly helpful for patients who must receive a drug over prolonged periods of time or who must receive several different drugs. These patients can have difficulty following a proper oral delivery regimen, and repeated injections are very discomforting to most patients. The drug or agent can be more effectively and comfortably administered by the application of dosing devices to the skin as infrequently as once or twice per week.
The skin provides an effective barrier to the passage of most substances including those which might have therapeutic effects. This is particularly so for the outer layer of skin which, in humans and most other warm-blooded animals, provides a most effective barrier to penetration. Other tissues in the body generally are more permeable, although this can depend on the particular nature of the tissue and drug in question. It is known that various substances can enhance the ability of drugs and agents to diffuse through the skin and other tissues. Several of these agents, typically surfactants, have been found to be effective but only after producing irreversible damage to the function or structure of the tissue that has been penetrated.
Dimethylsulfoxide (DMSO) has found to be an effective aid to the penetration of drugs and agents through the tissues for both localized drug administration and for introduction into the general body circulation. DMSO has been found to be a preferable penetration enhancing agent that does not impair the structure and function of tissue to the extent encountered with other penetration-enhancing substances. DMSO does, however, have several undesirable side effects. It causes foul taste and body odor, burning and erythema on the skin, activates latent virus infections within cells, reduces the relucency of the lens cortex and produces teratogenicity and tissue necrosis in animals. DMSO can cause liver damage if used extensively, and has the further disadvantage of penetrating any impurities or contaminants that are present as well as the drug or agent.
Dexamethasone is a steroid that is produced naturally in the body by the adrenal cortex, which steroids are called adrenal cortical steroids or corticoids. Some corticoids have the ability to effect the rate of metabolism of glucose and are therefore referred to by the name glucocorticoids. Glucocorticoids have been found useful in the depression of inflammation associated with arthritis and rheumatic diseases. Glucocorticoids are also useful in the treatment of dermatoses, drug reactions, bronchial asthma, lupus erythematosus, angioneuroedema, as well as in the treatment of leukemia. Examples of glucocorticoids include dexamethasone and betamethasone.
Dexamethasone and its salts are described in U.S. Pat. No. 3,007,923, which is herein incorporated by reference. It is understood that the term dexamethasone as herein applied also related to the base form and the various salts including 21-acetate, 21-phosphate, 21-phosphate disodium, 21-dimethylaminoacetate, 21-dimethyl butylrate, tetrahychoplithalate, etc. The application of dexamethasone, or its homologue betamethasone, by transdermal delivery systems has been impeded by the weak solubility of these compounds in most transdermal delivery compositions. It would be desirable to provide a transdermal delivery composition for dexamethasone and its homologues which would provide sufficient levels of the drug in a controlled form of administration and without the side effects encountered with the use of DMSO and other tissue penetration enhancers.
Transdermal delivery has been aided by the use of ultrasound technology. The ultrasound energy is applied to the transdermal delivery composition over the tissue and assists the diffusion of the composition past the tissue.
It is known that lodocaine can solubilize dexamethasone and other steroids for injectable solutions. These injectable solutions, however, suffer the drawbacks of other injectable solutions, namely bruising, damage by the needle, and discomfort.
U.S. Pat. No. 4,440,777 of Zupan discloses the use of eucalyptol as a transport agent for delivering active bio-affecting agents across the stratum corneum which includes dexamethasone.
U.S. Pat. No. 4,482,539 of Sandweiss et al discloses a cream-like gel formulation of betamethasone dipropionate.
However, the formulation is not suitable for use in sonic delivery systems.